The responses to drugs are affected by expectation, which is sensitive to prior drug experience. Expectation and conditioning can modulate the reinforcing effects of drugs of abuse. The mechanisms underlying these processes in humans are not well understood. We propose to investigate (1) the effects of expectation on the ability of a psychostimulant drug to increase extracellular dopamine (DA) and affect its behavioral effects and (2) the relation between habit learning and predicting reward of psychostimulant drugs on the effects of expectation. We will use positron emission tomography (PET) and [11C]raclopride (DA D2 receptor radioligand whose binding to D2 receptors is sensitive to competition by endogenous DA), to measure extracellular DA changes over a 3-year period. We will compare the responses in 24 cocaine-addicted subjects to those in 24 healthy controls. The study will compare the responses to methylphenidate (MP - psychostimulant drug which like cocaine increases extracellular DA by blocking DA transporters) when subjects expect to receive it versus when they expect to receive placebo. Our working hypotheses are: 1. The responses for expected to receive MP but do not receive it will results in a decrease in DA release in cocaine abusers and no changes in the control subjects. Since cocaine abusers have been conditioned to expect a drug that will recapitulate the high from cocaine whereas the controls have not. 2. Responses to MP whether expected or not expected will be attenuated in cocaine abusers when compared with controls. This is because chronic cocaine results in a hypodopaminergic state associated with decrease release of DA. 3. In cocaine abusers but not in controls the expectation of receiving MP should result in greater DA changes than when it's not expected. Preliminary work from our laboratory support our working hypotheses. The effects of drug expectation on the ability of psychostimulants to increase extracellular DA and the relationship to the reinforcing and addictive properties of stimulant drugs in humans are not known. A better understanding of the mechanisms underlying the effects of expectation on drug effects will help develop strategies that may be able to counteract the enhanced saliency that drugs of abuse have on the drug-addicted subjects and help prevent craving and relapse. PUBLIC HEALTH RELEVANCE: A better understanding of the mechanisms underlying the effects of expectation on drug effects will help develop strategies that may be able to counteract the enhanced saliency that drugs of abuse have on the drug-addicted subjects and help prevent craving and relapse.